Ibuprofen is one of the most commonly used pain relievers due to its effectiveness and high tolerability in doses of 200 mg and 400 mg. Based on the amounts of ibuprofen produced globally, a consumption of around 30 billion tablets per year can be assumed. The available dosage forms mostly contain ibuprofen in the acid form in view of the lower costs. Ibuprofen however has a poor and highly pH-dependent solubility. As the solubility increases only above a pH of 6.5, the active ingredient is dissolved and absorbed only in the intestinal tract but not in the stomach. Depending on the pH conditions in the intestinal tract, absorption may be further delayed due to physiological reasons. This is confirmed by numerous blood level tests which show a maximum blood level 1.5 to 2 hours after ingestion. This delay is a great disadvantage, because patients expect a fast onset of the analgesic effect when taking a pain reliever and tend to unnecessarily raise the dosage when the effect is delayed.
For the above reasons, numerous attempts have been made to accelerate the onset of action through pharmaceutical measures such as micronization of the active ingredient or development of particularly fast disintegrating film-coated tablets. However, such attempt could not improve the situation significantly, since the onset of action is mainly dependent upon the pH conditions in the intestinal tract. The pH in the upper-most part of the intestine (duodenum) lies predominantly between 5 and 6, but not above 6.5 as would be required to dissolve and absorb the active ingredient. Absorption can therefore take place only in lower parts of the intestine.
A clear improvement was however achieved through the use of ibuprofen salts with good water solubility such as ibuprofen lysinate, ibuprofen arginate and ibuprofen sodium salt. The distinct acceleration of absorption is astounding, since the ibuprofen salts are usually released under acidic conditions in the stomach which leads to precipitation of ibuprofen. The acceleration seems to be a consequence of the complex composition of the gastric juices whereby ibuprofen is precipitated in extremely fine form which facilitates rapid dissolution and resorption after passage to the duodenum. Numerous blood level tests have been published with the above salts, and they consistently gave maximum blood levels 35 to 40 minutes after ingestion under clinical conditions. However, the salts have to be produced in an additional step, and salt formation increases the molecular weight. As sodium ibuprofen can only be used in the form of the dihydrate, 256 mg of the salt are equivalent to 200 mg ibuprofen. To achieve the same dosage of 200 mg ibuprofen, 342 mg must be used in the case of ibuprofen lysinate and 370 mg in the case of ibuprofen arginate. Moreover, the sodium salt is about 2.8 times as expensive and the lysinate and the arginate are about 6 times as expensive, compared to the costs for ibuprofen. The potassium salt of ibuprofen is extremely hygroscopic and has never been used in commercial tablets. In view of the very low prices for ibuprofen pain relievers, the higher costs may be the main reason why the salts are seldom used commercially.
In WO 89/09053 alkali metal salts of ibuprofen are prepared by dissolving a predetermined amount of an alkali metal bicarbonate in an aqueous medium and then dissolving a predetermined amount of ibuprofen in the aqueous medium containing the bicarbonate composition. The alkali metal salt may be isolated from the aqueous media by evaporation or by a freeze drying process. The disclosed process produces large quantities of carbon dioxide (110 l per 1 kg ibuprofen) and intense foaming, and the salt must be isolated at high costs. Moreover, the disclosed tablets have to be produced in a costly multi-step process. It is apparent to the skilled person that those very expensive manufacturing processes are not appropriate for the production of ibuprofen dosage forms which can compete with the commercially available ibuprofen pain relievers.
WO 94/10994 discloses a powder or tablet composition comprising a water-soluble pharmaceutically acceptable salt of ibuprofen in intimate admixture with a pharmaceutically acceptable effervescent couple comprising at least one acid component and at least one carbonate component in which 95% or more of the ibuprofen salt has a crystal size from 180 microns to 800 microns, and in which the carbonate/acid weight ratio of the effervescent couple is 2-6 (to minimise precipitation of ibuprofen caused by reaction of salt with acid component) such that the pH of an aqueous solution formed from 1 g of the composition in 100 ml of purified water is greater than 5.0. The exemplified tablets contain sodium ibuprofen dihydrate in quantities of only 6.0-14.5% by weight. The sodium ibuprofen dihydrate is prepared in an expensive manner by dissolving 900 kg ibuprofen and 185.5 kg sodium hydroxide in 3,078 kg methylated spirit, and isolating and drying the salt.
U.S. Pat. No. 4,834,966 teaches compositions comprising ibuprofen, L-arginine and sodium bicarbonate in a weight ratio of (33-46):(34-51):(9-29). According to the disclosure, those compositions shall be useful in preparing soluble granulate compositions and permit rapid preparation of aqueous solutions at the moment of use. The disclosed granulates actually contain large quantities of further excipients. They are obtained by granulating ibuprofen and L-arginine with water at 90° C., subsequent drying and screening of the wet granulate and admixing the further components. Tablet formulations are not disclosed. U.S. Pat. No. 6,197,336 rather states that the inventors tried preparing tablets but found that it was impossible to obtain satisfactory results because the resulting tablets were to friable and subject to fragmentation during manufacturing and packaging.
The compositions described in U.S. Pat. No. 6,197,336 for use in fast dissolving tablets together with excipients comprise ibuprofen, 1.1-1.5 moles of arginine per mole of ibuprofen, 0.5-10% by weight of PVP and 5-10% by weight of a bicarbonate. Said composition is prepared by melting ibuprofen in a planetary mixer at 80° C. under continuous stirring, then adding arginine, PVP and boiling water, stirring the mixture for 10 minutes, slowly cooling down the creamy mass, and drying the obtained granular mass in a whirlpool static oven. In an alternative method, arginine is partially dissolved in water, then ibuprofen and PVP are added, the mixture is warmed under continuous stirring, and the creamy mass obtained is dried under vacuum and screened. The patent states that it is possible that during preparation of the composition and/or tablets, some interaction or reaction may occur between two or more components, but it is silent about the extent and type of such interaction. The disclosed tablets dissolve in about 10 minutes in a solution of pH 7.2 phosphate buffer at 37° C. The tablets containing 200 mg ibuprofen weigh 600 mg which is rather large for such dosage; tablets containing 400 mg ibuprofen weigh 980 mg which can hardly be swallowed. Moreover, the large quantity of expensive arginine required significantly increases the costs.
EP 0 478 838 A1 teaches preparations containing ibuprofen and conventional excipients which are characterized in that they contain the calcium salt of ibuprofen. The preparations may preferably also contain the sodium, potassium or ammonium salt of ibuprofen or ibuprofen in acid form. The preparations are obtained by treating ibuprofen with a solution of suspension of calcium oxide, calcium hydroxide or calcium carbonate, granulating the mixture and drying the obtained product. The excipients may be added before or after granulation. The calcium salt of ibuprofen is disclosed to improve the properties for tabletting, but it has also poor solubility and is thus not appropriate to produce tablets which permit rapid increase of blood level and fast onset of action.
WO 89/07439 teaches a process for regulating the absorption rate of drugs comprising a carboxylic acid derivative which is characterized in that the agent regulating the absorption rate comprises an alkaline compound selected from Mg(OH)2, MgO and Al(OH)3 and a mixture of these compounds. Example 11 describes a tablet having a tablet weight of 700 mg and containing 200 mg ibuprofen, 200 mg magnesium oxide and several further excipients.
WO 02/083105 discloses a composition containing an NSAID, preferably ibuprofen, a disintegration and dissolution agent such as a bicarbonate and an anti-precipitation agent. The document states that bicarbonate is believed to increase the solubility by promoting the formation of a salt and that the incorporated bicarbonate starts reacting with ibuprofen. In the most preferred process, ibuprofen is therefore mixed with a bicarbonate under non-aqueous conditions. The dissolution profile of a mixture of ibuprofen plus sodium bicarbonate (1:1 molar based) included therein shows in comparison to ibuprofen only a very weak improvement of the dissolved ibuprofen in 0.1 molar hydrochloric acid solution after one hour (15% instead of 10% dissolved ibuprofen).
In WO 97/30699, a solid non-effervescent compressed dosage form is disclosed which comprises an ibuprofen medicament and a carrier material comprising a compressible filler component combined with a disintegrating component wherein the ibuprofen medicament is present to an extent of 35% or more by weight of the dosage form, characterised in that the carrier material includes an alkali metal carbonate or bicarbonate in an amount such that the dosage form has a crushing strength in the range 6.5-15Kp and a disintegration time of less than 10 minutes, provided that the ibuprofen medicament does not contain a calcium salt of ibuprofen in combination with an alkali metal salt of ibuprofen. In all examples, the ibuprofen medicament is either sodium ibuprofen dihydrate or ibuprofen lysinate. The preparation of the salts is not disclosed. The sodium salt is disclosed to be particularly difficult to compress or pre-granulate. Preferably no liquid such as water is added to the formulation in any optional pre-granulation stage prior to compression. The carbonate or bicarbonate is used to improved the compressibility; the amounts utilized are usually too low to significantly improve dissolution whereas higher amounts of carbonate such as in Example 3 make the formulation extremely alkaline which may cause significant injury in the esophagus.
WO 2004/035024 teaches a non-effervescent tablet for oral administration of sodium ibuprofen comprising a tablet core and, if desired, a sugar or film coat on the tablet core, wherein the tablet core consists of 50 to 100% by weight of sodium ibuprofen hydrate and 50 to 0% by weight of auxiliary material component, based on the weight of the tablet core, and contains no lubricant and no disintegrant, the sodium ibuprofen hydrate having a water content of from 8 to 16% by weight of the hydrate. The auxiliary material component preferably comprises basic auxiliary materials and/or neutral to weakly acidic fillers that improve the compressibility. Prior to tabletization, the sodium ibuprofen hydrate is preferably granulated in dry form, optionally together with the auxiliary material or a part of the auxiliary material. Conventionally prepared sodium ibuprofen dihydrate was used which is about 3 times as expensive as the acid form.
In the U.S. Pat. Nos. 5,741,519 and 6,322,816 B1 solid solutions of ibuprofen, which are produced by means of an extruder, are described. The patents deal with the production of ibuprofen compositions in the form of a solid solution of the ibuprofen in a polymer matrix, and ibuprofen compositions produced by this process. The term “solid solution” is known to the skilled worker (see Chiou and Riegelmann, J. Pharm. Sci. 60 (9), (1971) 1281-1301) and means that an active ingredient is dissolved in a molten polymeric mass at elevated temperatures of 100° C. and higher. In the U.S. Pat. No. 6,322,816 B1 examples are therefore also described in which the proportion of water soluble polymer is 41-67%. The improvement of the solubility of the slightly soluble ibuprofen is thus achieved through the dissolution of the active ingredient in a water soluble polymer matrix and not through a solubilization with alkaline adjuvants. To solve the problem of low solubility by converting ibuprofen into highly water soluble salt compounds is excluded, because, for example, ibuprofen sodium is hygroscopic and can be tabletted only poorly (see 1, line 22-25). The high amount of water soluble polymeric matrix necessary raises the production costs significantly due to the high cost of the polymers. The 200 mg ibuprofen tablets described have an unacceptable tablet weight of about 800 mg. Besides the water soluble polymers, the adjuvant matrix comprises carbonates.
A fluid bed granulation of Ibuprofen aided by an aqueous binder solution of hydroxypropyl methylcellulose is described in the patent WO 00/27368. Sodium hydrogencarbonate aids the solution process of ibuprofen in water, but under the described production conditions and in the described amount of sodium hydrogencarbonate it is not capable of transforming the ibuprofen into its sodium salt.
U.S. Pat. No. 5,262,179 discloses non effervescent water soluble compositions of water soluble ibuprofen salts in which the unpleasant taste of the salt is masked by carbonates, mono hydrogen phosphates and tribasic citrates in aqueous solution. The teaching of the patent emanates from already existing salts of ibuprofen and does not concern the solubilization of ibuprofen with alkaline adjuvants. The alkaline additives have the task of so strongly buffering an ibuprofen salt solution that when drinking the pH does not drop so far in the mouth through saliva that the ibuprofen, which has a low solublitiy already at a pH value of 5-6, re-precipitates and leads to irritation of the oral mucosa. On page 3/39 it is described in detail that alkali metal carbonates and -phosphates cannot be used because in potential taste masking amounts, the resultant aqueous solution has an unacceptably high pH for oral administration.
In the U.S. Pat. No. 6,171,617 B1 granulations of ibuprofen with sodium carbonate, potassium carbonate and further basic adjuvants are described, wherein in each case water or mixtures of organic solvents and water are used. In order to obtain extensively water free granulates for effervescent tablets it has emerged under production conditions that production batches have to be dried under vacuum up to 24 hours. It is nowhere described that a reaction can be run for example with potassium carbonate under water free conditions or a conversion with sodium carbonate be directed such that with the conversion of 1 mole ibuprofen with one mole sodium carbonate and 2 mole water a ibuprofen sodium.2H2O/sodium hydrogencarbonate mixed salt is obtained, that without any drying can immediately be pressed into tablets. The utilization of hydrogencarbonate in contrast actually does not prove to be of any value at all since already at conditions of 60° C. the sodium hydrogencarbonate thermally disintegrates with formation of water, CO2 and sodium carbonate. It is also not described that the utilisation of two basic adjuvants clearly improves the physico-technical properties of the resulting solubilized ibuprofen granulates such as, dissolution, compression properties.
In addition it has emerged from the implementation of example 1 of this US-patent under production conditions that the sodium hydrogencarbonate disintegrates in a totally uncontrolled manner forming carbon dioxide and water and sodium carbonate and that no uniform product can be obtained. Under the conditions of example 2 the drying has to take place at temperatures from under 60° C., so that the drying process lasts 24 hours. The water has to be completely removed, because a solubilized ibuprofen sodium corresponding to this patent in the presence of acids leads to an unstable effervescent tablet. Due to the extremely long drying time no economically competitive effervescent tablets can accordingly be produced from this patent. The same negative observations were made with the conversion corresponding to example No. 3.
The U.S. Pat. No. 5,631,296 A discloses S(+)-ibuprofen pellets containing 90.0-99.0% by weight of S(+)-ibuprofen and 0.1-10% by weight of a basic compound selected from the group consisting of basic inorganic salts, dilute alkali metal hydroxide solutions and mixtures thereof. In Example 1 for 1 mole S(+)-ibuprofen only 0.04 mole sodium carbonate are used. Through this extremely low quantity an improvement of dissolution in a buffer with pH 7.2 is admittedly possible, in which ibuprofen would already quickly dissolve without the addition of alkaline adjuvants, however the named alkali amounts are substantially too low to amount to more rapid ibuprofen blood levels under in vivo conditions. The named quantities are absolutely not able to neutralize appreciable quantities of gastric juice, which acts on the drug form with the ingestion of such a medicament in the stomach. The US patent did not have the object to provide a particularly low cost ibuprofen drug form with a rapid blood level increase (low Tmax-value), rather to achieve a higher bioavailability (AUC=area under the blood level curve) of the effective S(+)-enantiomers through the use of S(+)-ibuprofen.
The U.S. Pat. No. 5,445,827 A relates to clear dissolving effervescent ibuprofen preparations and a process for their preparation. The patent did not have the object to describe (the preparation of) a very water soluble ibuprofen granulate in an efficient and cheap manner from insoluble ibuprofen According to claim 1 the patent exclusively relates to water free ibuprofen sodium, wherein a high excess of sodium hydrogencarbonate (19.4 mole pro 1 mole ibuprofen sodium) is sprayed in a fluid bed with a solution of ibuprofen sodium and PVP at 100°. Subsequently sodium carbonate is dissolved in water and likewise sprayed on the granulate. For the granulation of 22 kilos of ibuprofen sodium, 130 kilos of water have to be sprayed, which means for the production of the granulate, 1 mole ibuprofen sodium is treated with 72.2 mole water. Ibuprofen sodium is very hygroscopic and is present in general as a dihydrate. With the described process it is however the dihydrate which results first. It has to be dried very laboriously to the water free form. This production process of ibuprofen effervescent tablets is not economically competitive. Water free ibuprofen sodium can only be pressed with a large quantity of adjuvants such as described in the US patent and otherwise also shows extreme sticking to the tabletting tools.
In the US application 0055107A1 a pharmaceutical composition comprising a pharmaceutically active agent and a salt of that pharmaceutical active agent is described, which has the proviso that the composition does not contain hydrolyzed cellulose wherein that pharmaceutical active agent is a weak acid or weak base. As an example ibuprofen is named, which in an aqueous solution with potassium hydroxide is preferably neutralised to 50%, such that after drying of the solution a mixture of ibuprofen and the potassium salt of the ibuprofen arises. The production of such a mixture of ibuprofen acid and ibuprofen salt is very laborious and has the disadvantage that such a mixture only contains 50% solubilized ibuprofen. In order to achieve a rapid resorption of the ibuprofen it is very important that in the presence of gastric juice the active ingredient is completely present in solubilized salt form.
There is thus still a great demand for ibuprofen dosage forms which achieve a rapid onset of action, but can, nevertheless be produced at costs that are competitive with those of dosage forms comprising the acid form of ibuprofen.
In summary, in none of the above prior art documents a commercially convincing, cheap method for the production of highly water soluble ibuprofen granulates out of low solubility ibuprofen is presented. In a very expensive manner in an additional step an ibuprofen salt is firstly produced out of ibuprofen, or very expensive salts of ibuprofen are used such as, the lysine and arginine salts, or the ibuprofen is dissolved by means of an extrusion process in melting of expensive water soluble polymers. In most cases a fast onset of action of the ibuprofen is not guaranteed and the production costs of the tablets, which are in most cases too big, are not competitive with the production costs of film tablets of ibuprofen. In particular, however, in no case are solubilized ibuprofen granulates described, which are produced through conversion of especially at least two alkaline adjuvants, if necessary under addition of highly water soluble adjuvants with ibuprofen, or reference made to the in particular physico-technical advantages which are surprising for the man skilled in the art, such as compressibility of such solubilized ibuprofen compounds. With the exception of WO 2004/035024, not even the importance of the water content or whether it relates to the anhydrate or hydrate of the solubilized ibuprofen, is mentioned.